Treatment of inflammation

ABSTRACT

NEW SUBSTITUTED SALICYLIC ACIDS AND NON-TOXIC PHARMACEUTICALLY ACCEPTABLE SALTS, ESTERS, AND AMIDES DERIVED THEREFROM. THE SUBSTITUTED SALICYLIC ACIDS DESCRIBED HEREIN ARE USEFUL AS ANTI-INFLAMMATORY COMPOUNDS, ALSON INCLUDED HEREIN ARE METHODS OF PREPARING SAID SALICYLIC ACID COM POUNDS, PHARMACEUTICAL COMPOSITIONS HAVING SAID SALICYLIC ACID COMPOUNOS AS AND ACTIVE INGREDIENT AND METHODS OF TREATING INFLAMMATION BY ADMINISTERING THESE PARTICULAR COMPOSITIONS TO PATIENTS.

United States Patent O 3,632,760 TREATMENT OF INFLAMMATION Tsung-YingShen, Gordon L. Walford, and Bruce E. Witzel, Westfield, and HowardJones, Matawan, N.J., assignors t Merck & Co., Inc., Rahway, NJ. NoDrawing. Filed June 25, 1969, Ser. No. 836,623 Int. Cl. A6111 27/00 US.Cl. 424-230 2 Claims ABSTRACT OF THE DISCLOSURE New substitutedsalicylic acids and non-toxic pharmaceutically acceptable salts, esters,and amides derived therefrom. The substituted salicylic acids describedherein are useful as anti-inflammatory compounds. Also included hereinare methods of preparing said salicylic acid compounds, pharmaceuticalcompositions having said salicylic acid compounds as an activeingredient and methods of treating inflammation by administering theseparticular compositions to patients.

BACKGROUND OF THE INVENTION The development of anti-inflammatorycompounds in the past two decades has seen the growth of a great manynew drugs. Most of these have been steroids of ll-oxygenated pregnaneseries. These, while highly effective, have the drawback of causing manyside effects. There is a need in the market for equally effectivecompounds of much simpler structure and having less side effects.

SUMMARY OF THE INVENTION Generally, this invention relates to newsubstituted salicylic acid compounds and processes for producing thesame. This invention also relates to pharmaceutical compositionscontaining said salicylic acid compounds as an active ingredient and tomethods of treating inflammation by administering these particularcompositions to patients.

DESCRIPTION AND PREFERRED EMBODIMENTS This invention relates to newsubstituted salicylic acids and processes for producing the same. Morespecifically, this invention relates to substituted salicylic acids,esters, amides, anhydrides and non-toxic pharmaceutically acceptablesalts thereof. Still more specifically, this invention relatestocompounds having the following general formula:

wherein:

3,632,760 Patented Jan. 4, 1972 "ice R may be hydrogen, acyl (preferablyloweracyl such as formyl, acetyl, propionyl, butyryl, etc.), alkyl(preferably loweralkyl such as methyl, ethyl, propyl, isopropyl, butyl,pentyl, etc.), or alkoxy carbonyl (preferably loweralkoxy carbonyl suchas methoxy carbonyl, ethoxy carbonyl, hexoxy carbonyl, etc.);

R may be hydrogen, halogen (such as chloro, bromo, tfiuoro, or iodo,preferably fluoro or chloro), haloalkyl (preferably haloloweralkyl suchas trifluoromethyl, etc.), alkyl (preferably loweralkyl, such as methyl,ethyl, propyl, isopropyl, butyl, pentyl, etc.), cycloalkyl (cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl), or alkoxy(preferably loweralkoxy such as methoxy, ethoxy, isopropoxy or butoxy);

X may be hydrogen, alkyl, (preferably loweralkyl, such as methyl, ethyl,propyl, isopropyl, butyl, pentyl, etc.), hydroxy, alkoxy (preferablyloweralkoxy such as methoxy, acetoxy, isopropoxy or butoxy), acyloxy(such as benzoyloxyacetoxy or propionoxy), halogen (such as chloro,bromo, fluoro or iodo, preferably fluoro or chloro), haloalkyl(preferably haloloweralkyl such as trifiuoromethyl, etc.), nitro, amino,alkylamino (preferably loweralkylamino such as methylamino, propylamino,pentylamino, etc.), diloweralkylamino (dimethylamino, dibutylamino,propylpentylamino, etc.), acylamino (preferably loweracylamino such asformylamino, acetylamino, propionylamino, butyrylamino, etc.), mercapto,alkylmercapto (preferably loweralkylmercapto such as methylmercapto,ethylmercapto, etc.), alkylsulfinyl (preferably loweralkylsulfinyl suchas methylsulfinyl, ethyl sulfinyl, butylsulfinyl, etc.), alkylsulfonyl,(preferably loweralkylsulfonyl such as methyl sulfonyl, ethylsulfonyl,butylsulfonyl, etc.), sulfonamido, sulfonylamido, alkylaminoalkyl(preferably loweralkyl-arninoloweralkyl such as methylaminomethyl,ethylaminomethyl, etc.) dialkylaminoalky-l (preferablydiloweralkylaminoloweralkyl such as dimethylaminomethyl,diethylaminoethyl, etc.), hydroxyalkyl (preferably hydroxyloweralkylsuch as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.), alkoxyalkyl(preferably loweralkoxyloweralkyl such as methoxymethyl, methoxyethyl,ethoxyethyl, ethoxypropyl, etc.), mercaptoalkyl (preferablymercaptoloweralkyl such as mercaptomethyl, mercaptoethyl, etc.),alkylmercaptoalkyl (preferably loweralkylmercaptoloweralkyl such asmethylmercaptomethyl, ethylmercaptoethyl, ethylmercaptopropyl, etc.),cyano, carboXy, carboalkoxy (carbomethoxy, carboethoxy, etc.),carbamoyl, aryl (such as phenyl, halophenyl, tolyl, salicyl), aralkylsuch as benzyl, phenethyl, etc., aryloxy or arylalkoxy;

may be methyleneimino (-CH NH--), iminomethylene (NHCHmethylidenenitrilo (-CH=N),

nitrilomethylidene, (N=CH-), carbonylimino provided that the 0R group isalways ortho to the o H O-R group.

Representative compounds of this invention are as follows:

4- (p, 0, or m-fluorobenzylideneamino)-salicy1ic acid; S-(p, 0, orm-fiuorobenzylideneamino)-salicylic acid; 4-(p, 0, orm-fiuorobenzylamino)salicylic acid; S-(p, 0, orm-fluorobenzylamino)-salicylic acid;

4-(p, 0, or m-fluorobenzamido)-salicylic acid;

S-(p, 0, or m-fluorobenzamido)-salicylic acid;

4-(p, 0, or m-fluoram'linomethyl)-salicylic acid;

5-(p, 0, or m-fluoro anilinomethyD-salicylic acid;

4-(p, 0, or m-fluorophenyliminomethyl)-salicylic acid; 5-(p, 0, orm-fluorophenyliminomethyl)-salicylic acid;

and the corresponding salts, esters, anhydrides and amides.

This invention also relates to a method of treating inflammation inpatients using a compound of Formula I, particularly an especiallypreferred compound as the active constituent.

The compounds of the instant invention can be used to treat inflammationby reducing inflammation and relieving pain in such diseases asrheumatoid arthritis, osteoarthritis, gout, infectious arthritis andrheumatic fever. Furthermore, the compounds of the instant inventionhave better potency at the same dosage levels than similar typecompounds known in the prior art and exhibit a lower incidence of sideeffects.

The compounds of Formula I also have anti-pyretic and analgesic activityand would be administered and used in the same manner and in the samedosage ranges as if they were being used to treat inflammation asdiscussed further on.

The treatment of inflammation in accordance with the method of thepresent invention is accomplished by orally, rectally or parenterallyadministering to patients a composition of a compound of Formula I,particularly the especially preferred compounds in a non-toxicpharmaceutically acceptable carrier.

The non-toxic pharmaceutical carrier may be, for example, either a solidor a liquid. Exemplary of solid carriers are lactose, corn starch,gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba,sucrose, agar, pectin, cab-o-sil, and acacia. Exemplary of liquid canriers are peanut oil, olive oil, sesame oil and water. Similarly, thecarrier or diluent may include a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax.

Several pharmaceutical forms of the therapeutically useful compositionscan be used. For example, if a solid carrier is used, the compositionsmay take the form of tablets, capsules, powders, troches or lozenges,prepared by standard pharmaceutical techniques. If a liquid carrier isused, the preparation may be in the form of a soft gelation capsule, asyrup or a liquid suspension. Suppositories for rectal administrationand gels, lotions, etc. for topical application may be prepared in aconventional manner.

The active compounds of Formula I and of the compositions of thisinvention are administered in an amount sufficient to treatinflammation, that is to reduce inflammation. Advantageously, thecomposition will contain the active ingredient, namely, the compounds ofFormula I in an amount of from about 1 mg. to 100 mg. per kg. bodyweight per day (50 mg. to 7 g. per patient per day), preferably fromabout 2 mg. to 50 mg./kg. body weight per day (100 mg. to 3 g. perpatient per day).

The method of treatment of this invention comprises administering to apatient (animal or human), a compound of Formula I, particularly anespecially preferred compound admixed with a non-toxic pharmaceuticalcarrier such as exemplified above. The compounds of Formula I andparticularly the especially preferred compounds Will be administered inan amount of from 1 mg. to 100 mg./kg. body weight per day, preferablyfrom about 2 mg. to about 50 mg. per kilogram body weight per day andespecially from 4 mg. to 20 mg./kg. body weight per day. The most rapidand effective anti-inflammatory effect is obtained from oraladministration of a daily dosage of from about 4 to 20 mg./kg./day. Itshould be understood, however, that although preferred dosage ranges aregiven, the dose level for any particular patient depends upon theactivity of the specific compound employed. Also many other factors thatmodify the actions of drugs will be taken into account by those skilledin the art in the therapeutic use of medicinal agents, particularlythose of Formula I, for example, age, body weight, sex, diet, time ofadministration, route of administration, rate of excretion, drugcombination, reaction sensitivities and severity of the particulardisease.

The benzalaminosalicylic acids of this invention may be prepared byreacting an aminosalicylic acid with a substituted benzaldehyde.

The benzalaminosalicylic acid compounds may then be reduced to form thesubstituted benzylaminosalicylic acid compounds of this invention. Thebenzylaminosalicylic acid compounds may also be prepared via directbenzylation of sodium (or potassium) salicylate in ethanol containinganhydrous potassium carbonate.

The anilinomethylsalicylic acid compounds of this invention may beprepared by reacting a halo-methylsalicylic acid with a substitutedaniline. They may also be produced by reacting a methyl halogensubstituted methylsalicylate with a substituted aniline and bydrolyzingthe resultant methyl anilinomethylsalicylate.

The benzamidosalicylic acid compounds of this invention may be preparedby reducing a 4 (or 5) nitro methylanisole to form an amino methylanisole, reacting the amino methylanisole with a substitutedbenzoylhalide to form a benzamidoanisole, demethylating saidbenzamindoanisole to form a benzamidophenol and carboxylating saidbenzamidophenol, or via direct benzoylation of an aminosalicylic acid.

The phenyliminomethylsalicylic acid compounds of this invention may beproduced by reacting 4 (or 5)-formy1 salicylic acid with a substitutedaniline.

The compounds of this invention, where R is a group such that an esteris the final compounds (i.e. R=alkoxyl), are prepared 'by anyesterification procedure using an esterifying agent containing theappropriate R group. For example, the acid compounds of this inventionmay be reacted with the appropriate loweralkanol (preferably methanol)at elevated temperatures in the presence of a strong acid, such ashydrochloric acid, sulfuric acid, p-toluensulfonic acid, and the like,to form the desired ester.

The compounds of this invention, wherein R is a group such that an amideis the final compound (i.e., R is amino), may be prepared by anysuitable amidation reaction. For example, the acid compound (preferablythe methyl or ethyl ester) may be reacted with ammonia, ammoniumhydroxide, or an amide compound, at any suitable temperature (roomtemperature to reflux). When the amino group is desired, it is preferredto carry out the reaction with ammonia in a bomb at temperatures aboutC. to form the desired R (amino) compound. Preferably, when an amide isdesired which is derived from an amino acid, the following reactionsequence is followed: The benzoic acid final compound is reacted withisobutyl chlorocarbonate to form the mixed anhydride. This compound isin turn reacted with the desired amino acid ester and subsequentlyhydrolyzed to form the desired amide.

The final compound, wherein R is loweralkyl (preferably methyl), may beprepared by any appropriate alkylation reaction. For example, thecorresponding hydroxy benzoic acid, ester, or amide (preferably theester), may be reacted with a di(loweralkyl)sulfate (preferably dimethylsulfate) in the presence of a base (such as alkali carbonate) at anysuitable temperature (room temperature to reflux but preferably at ornear reflux) with subsequent acidification of the reaction mixture, suchas with hydrochloric acid, sulfuric acid, and the like, to form thedesired R compound.

The salts of the final acid compounds of this invention may be preparedby any of the well-known metathesis procedures. For example, the acidcompound may be reacted with an inorganic base, such as sodiumhydroxide, and the like. The anhydrides of this invention may beprepared by any of the well-known procedures in the art.

The following examples are presented to further illustrate theinvention:

EXAMPLE 1 Methyl S-(p-fluorobenzamido)-salicylate To methylS-aminosalicylate (0.01 m.) in pyridine at 10 C. is addedp-fluorobenzoyl chloride 0.01 m.), stirrings, over 10 minutes. Theresulting mixture is allowed to warm to room temperature, stirovernight, added to excess dilute hydrochloric acid, stirring, and themethyl 5- (p fluorobenzamido)-salicylate collected.

When other substituted benzoyl chlorides, e.g. with o-fluoro, m-fluoro,o-, 111-, and p-chloro, m-, and p-methoxy, 0-, m-, andp-trifluoromethyl, o-, m-, and p-nitro, o-, mand p-dimethylamino (orhydrochlorides), o, m-, and p-acetamido, o-, m-, and p-methylmercapto,o-, mand p-carbomethoxy, o-, mand p-phenyl, o-, m-, and p-benzyl, o-,mand p-phenoxy, o-, mand p-benzyloxy or o-, mand p-acetyl benzoylchloride are used, the corresponding substituted S-benzamidosalicylateis obtained.

When the 3-chloro, 3-methoxy, 3-methyl, and 4-fluoro analogs ofS-aminosalicylate are used in the above example in place of methylS-aminosalicylate, the corresponding substituted salicylates areobtained. When methyl 4-amino analogs are used in the above procedurethe corresponding substituted salicylates are obtained.

The above benzoylations may be carried out by other means known to thosein the art, such as addition of the benzoyl halide to an aqueous,nitrogen covered solution of a metal salt, such as sodium or potassium,of the sal- ,icylic acid with concomitant addition of base to maintainthe pH of the reaction mixture at 8. Only those benzoyl halides withgroups compatible with aqueous hydroxide are used in this procedure.

EXAMPLE 2 -(p-fluorobenzylideneamino)-salicylic acid A mixture ofS-aminosalicylie acid (0.005 m.) and p-fluorobenzaldehyde (0.005 m.) inethanol (150 ml.) is heated, protected from moisture, for 5 hours,concentrated and cooled, and the 5-(p-fluorobenzylideneamino)-salicylicacid collected.

A trace of p-toluene sulfonic acid may be employed as a catalyst in theabove reaction.

When o-, and m-fluorobenzaldehyde, o-, mand p-chlorobenzaldehyde, o-,m-, and p-methylbenzaldehyde, p-dimethylaminobenzaldehyde, o-, mandp-trifluoromethylbenzaldehyde, p-acetamidobenzaldehyde, o-, m-, andpmethylthiobenzaldehyde, p-cyanobenzaldehyde, mandp-benzyloxybenzaldehyde, biphenylcarboxaldehyde, benzylbenzaldehyde,p-phenoxybenzaldehyde, p-acetylbenzaldehyde,p-methylsulfonylbenzaldehyde, dichlorobenzaldehyde,trichlorobenzaldehyde, 2,3,4,5-tetramethylben zaldehyde, orp-carbomethoxybenzaldehyde are used in place of p-fluorobenzaldehyde inthe above procedure, the corresponding substituted benzalaminosalicylicacids are obtained.

When the 3-chloro, 3-methoxy, 3-methyl, or 4-fluoro analogs ofS-aminosalicylic acid are used in place of 5- aminosalicylic acid in theabove example, the corresponding substituted salicylic acids areobtained.

When 4-aminosalicylic acid and its analogs are used in place ofS-aminosalicylic acid in the above procedure, the correspondingsubstituted salicylic acids are obtained.

EXAMPLE 3 5-(p-fiuorobenZylamino)-salicylic acid.

A mixture of 5- (p-fluorobenzylideneamino)-salicylic acid (0.01 m.),ethanol (50 ml.) and 5% palladium on charcoal (0.5 g.) is reacted in a40 p.s.i. hydrogen atmosphere at room temperature until 0.01 m. hydrogenhas been absorbed, the mixture filtered, the cake washed well withethanol, the filtrates combined and concentrated in vacuo to5-(p-fluorobenzylamino)-salicylic acid.

The above reduction may be achieved using metal hydrides as the reducingagent.

The above product may also be obtained via direct p-fluorobenzylation ofsodium (or potassium) S-aminosalicylate in ethanol containing anhydrouspotassium carbonate.

When the substituted benzylideneamino compounds of Example 2 which arecompatible with the reduction conditions are treated with hydrogen asabove, the corresponding substituted S-benzylaminosalicylic acids areobtained.

EXAMPLE 4 S-(p-fluoroanilinomethyl)-salicylic acid A mixture of methylS-chloromethylsalicylate (0.01 ml.), and p-fluoroaniline (0.01 m.) inmethanol (25 ml.) containing anhydrous potassium carbonate is heated for8 hours, cooled, filtered, the cake 'washed well with fresh methanol,the combined filtrates concentrated in vacuo, the residue taken up inchloroform, dried, filtered, the chloroform removed in vacuo, and theresidue chromatographed on a silica gel column using an ether-petroleumether system (v./v. 10100% ether) as eluant yielding methylS-(p-fluoroanilinomethyl)-salicylate. Hydrolysis of the ester yieldsS-(p-fiuoroanilinomethyl)-salicylic acid.

When o-, and m-fluoroaniline, the toluidines, the anisidines, o-, mandp-chloroaniline, the trifiuoromethylanilines, o-, mand p-nitroaniline,o-, mand p-methylthioaniline, methyl p aminobenzoate, thebiphenylamines, p benzylaniline, 4 aminophenylether, and 4-benzyloxyaniline are used in place of p-fluoroaniline in the abovereaction, the corresponding 5- (anilinomethyl)-' salicylate is obtained.

EXAMPLE 5 3-trifluoromethyl-4-nitroanisole A stainless steel linedshaker is charged with 6-nitrom-anisic acid (0.1 m.) under a nitrogenatmosphere, the system cooled in Dry Ice, sulfur tetrafluoride (0.5 m.)condensed into the tube, and the mixture then heated at C. for 8 hours.After cooling, the tube is vented, the material taken up in chloroform,the chloroform mixture washed with dilute bicarbonate solution, thechloroform dried, filtered, concentrated in vacuo, and the residuechromatographed on a silica gel column using an ether-petroleum ethersystem (v./v. 0-80% ether) an eluant to yield3-trifluoromethyl-4-nitroanisole.

EXAMPLE 6 4(p-fluorobenzamido -3-trifluoromethylanisole A mixture of4-nitro-3-trifiuoromethylanisole (0.1 m.), and 5% palladium on charcoalcatalyst (2 g.) in ethanol (500 ml.) is reacted with hydrogen (40p.s.i.) at room temperature. When hydrogen uptake has stopped, themixture is filtered, the ethanol removed in vacuo, anhydrous pyridine(300 ml.) added, and the resulting mixture treated with p-fiuorobenzoylchloride as per Example 1, 4-(p-fluorobenzamido) 3trifluoromethylanisole is obtained.

When the substituted benzoylhalides of Example 1 are used in place ofp-fiuorobenzoyl chloride in Example 6, above, the correspondinglysubstituted benzamidoanisole is obtained.

When the free amino compound obtained above is benzylated withsubstituted benzylhalides as in Example 3, or using pyridine as thesolvent base, the cone spondingly substituted benzylamino anisole isobtained.

EXAMPLE 7 p- (4-fiuorobenzamido -m-trifluoromethylphenol A mixture ofp-(4-fluorobenzamido)-m-trifiuoromethylanisole (5 g.) and pyridinehydrochloride (25 g.) under a dry nitrogen atmosphere is placed in anoil bath set at 230, kept 10 minutes, cooled, and the mixture extractedwith chloroform. The chloroform extracts are washed with Water, dried,concentrated in vacuo, and the residue chromatographed on a silica gelcolumn using a methanolmethylene chloride (v./v. 50% methanol) system aseluant to yield p-(4-fluorobenzamido)-m-trifluoromethylphenol.

When the other substituted benzamido and substituted benzylaminoanisolesof Example 6, and 4-amino-3-trifluoromethylanisole from Example 6 arereacted with pyridine hydrochloride as above, the corresponding phenolsare obtained. Other standard procedures for demethylation may also beemployed.

EXAMPLE 8 (p-fluorobenzamido -4-trifiuoromethylsalicylic acid Anintimately ground mixture ofp-(4-fiuorobenzamido)-3-trifiuoromethylphenol (5 g.) and anhydrouspotassium carbonate (15 g.) is heated at 200 C. in a 1200- 1400 psi.carbon dioxide atmosphere for 8 hours. The mixture is cooled, added towater (300 ml.), stirred, filtered, and the filtrate neutralized withdilute hydrochloric acid to yieldS-(p-fiuorobenzamido)-4-trifiuoromethylsalicylic acid.

When the phenols of Example 7 are reacted with carbon dioxide as above,the correspondingly substituted salicylic acids are obtained.

EXAMPLE 9 5- (p-fiuorobenzylideneamino) -4-trifluoromethyl salicylicacid When 5-amino-4-trifiuoromethylsalicylic acid is reacted withp-fluorobenzaldehyde as per Example 2,5-(p-fiuorobenzylideneamino)-4-trifluoromethyl salicylic acid isobtained.

When the benzaldehydes of Example 2 are used in place ofp-fluorobenzaldehyde in the above case, the correspondingly substitutedS-benzylideneaminosalicylic acid is obtained.

EXAMPLE 10 Methyl 5 (p-hydroxybenzylamino -salicylate When methylS-(p-methoxybenzylamino)-salicylate is reacted with pyridinehydrochloride as per Example 7, methyl5(p-hydroxybenzylamino)-salicylate is obtained.

EXAMPLE l1 Methyl 5-(p-mercaptobenzamido)-salicylate When methyl5-(p-methylthiobenzamido)-salicylate is reacted with pyridinehydrochloride as per Example 7 methyl 5- (p-mercaptobenzamido-salicylate is obtained.

EXAMPLE 12 Methyl-S- (p-aminobenzamidosalicylate) When methyl5-(p-nitrobenzamido)-salicylate in methanol is reacted with hydrogen asper the reduction condi tions of Example 6, methyl5-(p-aminobenzamidosalicylate is obtained.

When the nitro compounds of Examples 1 and 3 are used in the aboveprocess, the corresponding amino substituted compounds are obtained.

EXAMPLE 13 5-(p-methylsulfinylbenzamido)-salicylic acid To5-(p-rnethylthiobenzamido)-salicylic acid (0.01 m.) in 1:1methanol-acetone, ice-cooling and stirring, is added sodiummetaperiodate (0.01 m.) in a minimum of water, and the reaction mixturestirred until precipitation of sodium iodate is completed. The mixtureis filtered, the filtrate concentrated in vacuo, the residue taken up inchloroform, filtered and concentrated in vacuo to crude 5-(p-methylsulfinylbenzamido -salicylic acid.

When two equivalents of metaperiodate are used and the reaction carriedout at ca. 50 C., S-(p-methylsulfonylbenzamido)-salicylic acid isobtained.

When the methylmercapto compounds of Examples 2 and 3 are oxidized asabove, the corresponding methylsulfinyl and methylsulfonyl analogs areobtained.

EXAMPLE 14 5-(p-carboxybenzylaminosalicylic acid To a solution ofpotassium hydroxide (0.05 m.) in water ml.) is added5-(p-carbomethoxybenzylamino) salicylic acid (0.01 m.), stirring, andthe resultant mixture heated gently for solution, allowed to stir atroom temperature for 5 hours, filtered, the pH of the filtrate adjustedwith dilute hydrochloric acid, and the S-(p-carboxybenzylamino)salicylic acid collected.

EXAMPLE l5 S-(p-carbamylbenzylamino -salicylate To a mixture of methylS-(p-cyanobenzylamino)-salicylate (2 g.) in methylene chloride (25 ml.),stirring, is added manganese dioxide (12 g.) and the mixture stirred for70 hours at room temperature. The mixture is filtered, the cake WashedWell with warm methylene chloride, the filtrates concentrated in vacuoto a residue, the residue chromatographed on a silica gel column using amethanolmethylene chloride system (v./v. 0-80% methanol) as eluant toyield methyl 5-(p-carbamylbenzylamino)-salicylate.

The nitrile may also be converted to the amide using concentratesulfuric acid in the cold.

EXAMPLE 16 Methyl 5- (p-fluorobenzamido)-o-anisate EXAMPLE 172-acetoxy-5- (N-acetyl-p-acetoxybenzylamino) benzoic acid To a solutionof 5-(p-hydroxybenzylamino)-salicylic acid (2 g.) in pyridine (15 ml.)is added acetic anhydride (28 ml.) and the resultant mixture heated onthe steam cone for 5 hours, protected from moisture. On cooling, themixture is added to water (300 ml.) with stirring, the aqueous systemextracted well with chloroform, the chloroform layer washed with dilutehydrochloric acid, water, dried over magnesium sulfate, filtered andconcentrated in vacuo to2-acetoxy-5-(N-acetyl-p-acetoxybenzylamino)-benzoic acid.

EXAMPLE 18 m-Methoxymethylbenzoic acid m-Carbomethoxybenzylbormide (0.02m.) is added to sodium methoxide (0.04 m.) in methanol and the mixtureheated gently for several hours. Water is added, the mixture heated toboil away methanol, filtered and acidified with dilute hydrochloric acidto yield m-methoxymethylbenzoic acid.

When potassium methylmercaptide is used in place of sodium methoxide inthe above reaction, m-methylthiomethylbenzoic acid is obtained.

When m-carbomethoxybenzyl bromide is reacted with sodium benzylate orpotassium benzylmercaptide, and the product hydrolyzed as above,-m-benzyloxyrnethyland rn-benzylthiomethylbenzoic acids are obtained.

EXAMPLE 19 5- (m-methoxymethylbenzamido) -salicylic acidm-Methoxymethylbenzoic acid (2 g.) is added gradually to stirred thionylchloride (20 ml.), heated gently until reaction ceases, and the excessthionyl chloride removed in vacuo. Anhydrous benzene (30 ml.) is aded,and then removed in vacuo to get rid of traces of thionyl chloride. Theresidual rn-methoxymethylbenzoyl chloride is used as in the reactionwith 5-aminosalicylic acid, via the procedure of Example 1, to yieldS-(m-methoxymethylbenzamido)-salicylic acid.

When m-methylthiomethylbenzoic acid, m-benzyloxymethylbenzoic acid, andm-benzylthiomethylbenzoic acid of Example 18 are used in place ofm-methoxymethylbenzoic acid, above, 5-(m-methylthiomethylbenzamido)salicylic acid, 5- (m-benzyloxymethylbenzamido)-salicylic acid, and5-(m-benzylthiomethylbenzamido)-salicylic acid are obtained,respectively.

Phosphorus pentachloride in phosphorous oxychloride may be used in placeof thionyl chloride in the above reaction.

EXAMPLE 20 Methyl 5- (m-hydroxymethylbenzamido)-salicylate A mixture ofmethyl 5-(m-benzyloxymethylbenzamido)-salicylate (0.01 m.), methanol(100 ml.) and 5% palladium on charcoal (0.5 g.) is subjected to a 40p.s.i. hydrogen atmosphere; at room temperature, removed when 0.01 in.hydrogen has been absorbed, filtered, concentrated in vacuo, the residuechromatographed on a silica gel column using an ether-petroleum ethersystem (v./v. 590% ether) as eluant to yield methyl5-(m-hydroxymethylbenzamido -salicylate.

When methyl 5-(m-benzylthiomethylbenzamido)-salicylate is reduced asabove, methyl S-(m-mercaptomethylbenzamido) salieylate is obtained.

EXAMPLE 21 Methyl 5- (p-aminomethylbenzylamino -salicylatedihydrochloride Methyl 5-(p-cyanobenzylamino)-salicylate (0.01 m.) inacetic acid (100 ml.) is reduced at room temperature under a 40 p.s.i.hydrogen atmosphere, using 0.5 g. platinum oxide as a catalyst. When thetheoretical amount of hydrogen is consumed, the mixture is filtered, thesolvent removed in vacuo, the residue taken up in chloroformether,filtered, anhydrous ethereal-hydrogen chloride added and the methyl5-(p-aminomethylbenzylamino)- salicylate dihydrochloride collected.

EXAMPLE 22 Methyl 5- p-dimethylaminomethylb enzylamino salieylate Amixture of methyl 5-(p-aminomethylbenzylamino)- salieylate (0.008 m.),37% formaldehyde (6 ml.), dried 1,2-dimethoxyethane (120 ml.), glacialacetic acid (50 ml.) and Raney nickel (2 tsp.) is treated with hydrogen(40 p.s.i.) at room temperature. When uptake is completed, the mixtureis filtered, the cake Washed well with fresh dimethoxy ethane, thecombined filtrates distributed between chloroform-dilute sodiumbicarbonate solution, the chloroform layer dried, concentrated, and theresidue chromatographed on a silica gel column using a methanolmethylenechloride system (v./v. -90% methanol) as eluant to yield methyl-(p-dimethylaminomethylbenzylamino) -salicylate.

EXAMPLE 23 Methyl 2-carboxy-4-(p-fluorobenzamido)-phenyl carbonate To amixture of 5-(p-fiuorobenzamido)-salicylic acid (0.01 m.),dimethylaniline (0.02 m.) and benzene (30 ml.) is added methylchloroformate (0.01 In.) over one hour with constant shaking andcooling. When the odor of the chlorocarbonate is absent, hydrochloricacid (1 N, ml.) is added and the mixture filtered. The benzene layer isseparated, dried, filtered, and the benzene removed in vacuo to yieldmethyl 2-carboxy-4-(p-fluorobenzarnido)-phenyl carbonate.

EXAMPLE 24 N- 3-carboxy-4-hydroxybenzal) -p-fluoroaniline When5-formylsalicylic acid (0.005 m. and p-fluoroaniline are reacted as perExample 2, N-(3-carboxy-4- hydroxybenzal)-p-fluoroaniline is obtained.

When other substituted aniline compounds are used in place ofp-fluoroaniline in the above procedure, the corresponding substitutedphenyliminomethylsalicylic acids are obtained.

EXAMPLE 25 Methyl 5- (p-fluorobenzylamino -salicylate To a mixture of5-(pfluorobenzylamino)-salicylic acid (0.015 m.) and absolute methanol(50 ml.), is added slowly, with stirring, concentrated sulfuric acid(2.0 ml.). The mixture is then heated gently for 18 hours. Excessmethanol is removed by evaporation in vacuo, the residue partitionedbetween chloroform-water, the chloroform layer washed with dilute sodiumbicarbonate solution, water, dried, filtered and concentrated to yieldmethyl 5- p-fluorobenzylamino -salicylate.

When the S-(p-fluorobenzylamino)salicylic acid of the above procedure isreplaced by any of the other salicylic acid compounds of this invention,the corresponding methyl ester is prepared.

When methanol in the above procedure is replaced by other appropriatealcohols such as ethanol, propanol, isopropanol, butanol, isobutanol,2-methoxyethanol or 2- ethoxyethanol, etc., the corresponding ester isprepared.

Diazo compounds, such as diazomethane, may also be used to prepare thecorresponding ester, and in some cases is preferred.

EXAMPLE 26 4-(p-fiuorobenzylamino)-salicylamide A mixture of methyl4-(p-fluorobenzylamino)-salicylate and concentrated ammonium hydroxidefivefold excess) is heated at 100 C. in a sealed tube for six hours.Afer cooling, water is added and the4-(p-fiuorobenzylamino)-salicylamide collected.

When monomethylamine, dimethylamine, ethylamine, diethylamine,morpholine, piperidine, etc. are used in place of ammonium hydroxide,the corresponding amides are obtained.

EXAMPLE 27 Sodium 5-(p-fluorobenzamido)-salicylate When5-(p-fluorobenzamido)-salicylic acid is replaced by the other salicylicacid compounds of this invention, the corresponding salt is obtained.

We claim: 1. A method of treating inflammation Which comprises 1 1administering to a patient 1 mg. to 100 mg. per kg weight per day of acompound of the formula:

I C R -Q Xn-s) R3 OR;

wherein R is hydroxy;

R is hydrogen or acetyl;

R is hydrogen;

X is halogen;

Y is carbonylimino or iminocarbonyl provided that the 0R group is alwaysortho to the 0 ll C-R group and the Y group is in the 4- or 5-positionof the 20 salicylic acid radical.

. body References Cited UNITED STATES PATENTS 3,228,831 1/1966 Nicholsonet al. 424-317 FOREIGN PATENTS 512,756 5/1955 Canada 26052O STANLEY J.FRIEDMAN, Primary Examiner US. Cl. X.R.

